Real-time HPLC-MS reaction progress monitoring using an automated analytical platform

An automated reaction monitoring system capable of unattended sample aliquoting and dilution, as well as immediate quantification and identification of reaction components via HPLC-MS has been developed. The device allows for facile reaction progress analysis, enabling mechanistic studies and serving as a primary process analytical technology (PAT) for reaction monitoring. The sampling sequence utilizes in line mixing to provide highly reproducible and accurate reaction profiles. To demonstrate the flexibility and robustness of this tool, progress curves have been acquired for three distinct reactions; namely a Cu-(I)-catalysed azide-alkyne cycloaddition which is difficult to quench due to very high catalyst activity, a Suzuki cross-coupling reaction that proves challenging to monitor due to heterogenous reagents, and a complex multicomponent cascade reaction that generates multiple regioisomers that are difficult to quantify by online spectroscopic methods.